Human hemoglobin disorders cause much morbidity and mortality throughout the world. New methods of studying genes, particularly restriction endonuclease analysis by gel electrophoresis and blotting, and sequencing of DNA in molecular clones, have allowed much recent progress in the study of normal human globin genes and their alterations in these disorders. This proposal describes analysis of specific DNA defects in beta thalassemia, study of the switchover from fetal to adult hemoglobin synthesis using nondeletion types of hereditary persistence of fetal hemoglobin, and comparison of mild and severe thalassemia, and investigation of alpha-globin gene expression in alpha-gene variants. These studies will relate results by their newer technics to those obtained by hematological, genetic, and biochemical methods. The long-term objective of this project is to provide information which will be of use in diagnosis and therapy of patients with hemoglobin disorders.